Neutral Metoclopramide Induces Tumor Cytotoxicity and Sensitizes Ionizing Radiation of a Human Lung Adenocarcinoma and Virus Induced Sarcoma in Mice

Abstract

Radiation induced cytotoxicity was potentiated by neutralized metoclopramide (nMCA; Neu-Sensamide^TM, Oxigene Inc) when a human lung adenocarcinoma (H2981) transplanted into scid mice and an adeno-type 12 virus induced mouse sarcoma (A12B3) inoculated into CBA mice were exposed in vivo to low dose radiation at single doses of 1 and 2 Gy respectively. However. when the radiation dose was increased to 6, 10 or 18 Gy (single dose) and combined with a single dose nMCA (2 mg/kg), tumor cytotoxicity was not sensitized by the combination treatment. A fractionated dose of ionizing radiation (3 × 1 Gy) in combination with nMCA at a repeated dose of 3 × 10 mg/kg body weight (1 dose/day, i.m.) significantly increased cytotoxicity in H2981 compared with radiation given alone. nMCA alone also had a statistically significant dose dependent cytotoxic effect on H2981 growth when it was administered as repeated doses (8 doses) at 2 mg/kg or 10 mg/kg (I dose every second day), and a similar result was achieved at 20 mg/kg but not at 2 and 10 mg/kg in the A12B3 tumor. In addition, the tumor volume at the start of treatment was important for the anti-tumor effect of nMCA (i.e. the larger initial tumor volume gave less effect on tumor growth). Taken together. our data propose that the mode of action of nMCA is different from radiation, and hence the two mechanisms are at least additive when in combination with lower radiation doses. The data further suggest that the cytotoxic mechanism is consistent with potentiating apoptosis because low and repeated doses of radiation (1–2 Gy), which are known to increase cytotoxicity by apoptosis, are sensitized by nMCA but not high doses and nMCA has more potent anti-tumor effects against H2981 tumors which have a higher constitutive apoptotic fraction of cells than A12B3.